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Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.
Garg, Garima Muschaweckh, Andreas Moreno, Helena Vasanthakumar, Ajithkumar Floess, Stefan Lepennetier, Gildas Oellinger, Rupert Zhan, Yifan Regen, Tommy Hiltensperger, Michael
Garg, Garima
Muschaweckh, Andreas
Moreno, Helena
Vasanthakumar, Ajithkumar
Floess, Stefan
Lepennetier, Gildas
Oellinger, Rupert
Zhan, Yifan
Regen, Tommy
Hiltensperger, Michael
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2019-02-12
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Summary Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and “toxic” gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
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2211-1247